This application claims benefit to DE 101 43 272.0 filed Sep. 4, 2001 and U.S. provisional application No. 60/332681 filed Nov. 14, 2001.
The present invention relates to new dihydropteridinones of general formula (I) 
wherein the groups X, R1, R2, R3, R4, R5, R6 and R7 have the meanings given in the claims and specification, the isomers thereof, processes for preparing these dihydropteridinones and the use thereof as pharmaceutical compositions.
Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity. WO 01/019825 describes the use of pteridinone derivatives for the treatment of neoplastic and viral diseases. The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.
The aim of the present invention is to prepare new compounds with an antiinflammatory and antiproliferative activity.
Surprisingly it has been found that compounds of general formula (I) wherein the groups X and R1 to R7 have the meanings given hereinafter act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention may be used for example to treat diseases connected with the activity of specific cell cycle kinases and characterised by excessive or abnormal cell proliferation.
The present invention therefore relates to compounds of general formula (I) 
wherein
R1 denotes a group selected from among hydrogen, NH2, XH, halogen and a C1-C3-alkyl group optionally substituted by one or more halogen atoms,
R2 denotes a group selected from among hydrogen, CHO, XH, xe2x80x94Xxe2x80x94C1-C2-alkyl and an optionally substituted C1-C3-alkyl group,
R3, R4 which may be identical or different denote a group selected from among optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, xe2x80x94X-aryl, xe2x80x94X-heteroaryl, xe2x80x94X-cycloalkyl, xe2x80x94X-heterocycloalkyl, xe2x80x94NR8-aryl, xe2x80x94NR8-heteroaryl, xe2x80x94NR8-cycloalkyl and xe2x80x94NR8-heterocycloalkyl, or a group selected from among hydrogen, halogen, COXR8, CON(R8)2, COR8 and XR8, or
R3 and R4 together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,
R5 denotes hydrogen or a group selected from among optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl and xe2x80x94C3-C6-cycloalkyl, or
R3 and R5 or R4 and R5 together denote a saturated or unsaturated C3-C4-alkyl bridge which may contain 1 to 2 heteroatoms,
R6 denotes optionally substituted aryl or heteroaryl,
R7 denotes hydrogen or xe2x80x94COxe2x80x94Xxe2x80x94C1-C4-alkyl, and
X in each case independently of one another denotes O or S,
R8 in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred compounds of formula (I) are those wherein
X and R6 have the meaning indicated, and
R1 denotes hydrogen,
R2 denotes a group selected from among a CHO, OH, and CH3 group,
R3, R4 which may be identical or different denote a group selected from among hydrogen, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, or
R3 and R4 together denote a C2-C5-alkyl bridge,
R5 denotes a group selected from among optionally substituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C3-C6-cycloalkyl and C3-C6-cycloalkenyl, or
R3 and R5 or R4 and R5 together denote a saturated or unsaturated C3-C4-alkyl bridge which may contain 1 to 2 heteroatoms, and
R7 denotes hydrogen,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred compounds of formula (I) are those wherein
R1-R5, R7, R8 and X have the meaning indicated, and
R6 denotes a group of general formula 
wherein
n denotes 1, 2, 3 or 4,
R9 denotes a group selected from among optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, xe2x80x94CONHxe2x80x94C1-C10-alkylene, xe2x80x94O-aryl, xe2x80x94O-heteroaryl, xe2x80x94O-cycloalkyl, xe2x80x94O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among xe2x80x94Oxe2x80x94C1-C6-alkyl-Q1, xe2x80x94CONR8xe2x80x94C1-C10-alkyl-Q1, xe2x80x94CONR8xe2x80x94C2-C10-alkenyl-Q1, xe2x80x94CONR8xe2x80x94Q2, halogen, OH, xe2x80x94SO2R8, xe2x80x94SO2N(R8)2, xe2x80x94COR8, xe2x80x94COOR8, xe2x80x94N(R8)2, xe2x80x94NHCOR8, CONR8OC1-C10 alkylQ1 and CONR8OQ2,
Q1 denotes hydrogen, xe2x80x94NHCOR8, or a group selected from among an optionally substituted xe2x80x94NH-aryl, xe2x80x94NH-heteroaryl, aryl, heteroaryl, C3-C8-cycloalkyl-and heterocycloalkyl group,
Q2 denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, C3-C8-heterocycloalkyl, C3-C8-cycloalkyl- and C1-C4-alkyl-C3-C8-cycloalkyl group,
R10 which may be identical or different denotes a group selected from among optionally substituted C1-C6-alkyl , C2-C6-alkenyl and C2-C6-alkynyl, xe2x80x94Oxe2x80x94C1-C6-alkyl, xe2x80x94Oxe2x80x94C2-C6-alkenyl, xe2x80x94Oxe2x80x94C2-C6-alkynyl, C3-C6-heterocycloalkyl and C3-C6-cycloalkyl, or a group selected from among hydrogen, xe2x80x94CONH2, xe2x80x94COOR8, xe2x80x94OCON(R8)2, xe2x80x94N(R8)2, xe2x80x94NHCOR8, xe2x80x94NHCON(R8)2, xe2x80x94NO2 and halogen, or
adjacent groups R9 and R10 together denote a bridge of general formula 
Y denotes O, S or NR11,
m denotes 0, 1 or 2
R11 denotes hydrogen or C1-C2-alkyl, and
R12 denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, xe2x80x94C1-C3-alkyl-phenyl, xe2x80x94C1-C3-alkyl-pyridyl, xe2x80x94C1-C3-alkyl-pyrazinyl, xe2x80x94C1-C3-alkyl-pyrimidinyl and xe2x80x94C1-C3-alkyl-pyridazinyl,
R13 denotes C1-C6-alkyl,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are compounds of formula (I) wherein
R3-R6, R8 and X have the meaning indicated, and
R1 denotes hydrogen,
R2 denotes CH3, and
R7 denotes hydrogen,
optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The invention further relates to compounds of formula (I), wherein X and R1-R7 have the meanings indicated, for use as pharmaceutical compositions.
Of particular importance according to the invention are compounds of formula (I), wherein X and R1-R7 have the meaning indicated, for use as pharmaceutical compositions with an antiproliferative activity.
The invention also relates to the use of a compound of formula (I), wherein X and R1-R7 have the meaning indicated, for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
The invention also relates to a method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective amount of a compound of formula (I), wherein X and R1-R7 have the meanings indicated.
The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), wherein X and R1-R7 have the meanings indicated, or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
The invention also relates to a process for preparing a compound of general formula (I), 
wherein
R1-R7 and X are as hereinbefore defined, characterised in that a compound of general formula (II) 
wherein
R1-R5 and X are as hereinbefore defined and L is a leaving group, is reacted with an optionally substituted compound of general formula (III) 
wherein
R6 and R7 are as hereinbefore defined.
The invention also relates to a compound of formula (II), 
wherein
R1-R5 and X are as hereinbefore defined. Compounds of formula (II) are important intermediate products for preparing the compounds of formula (I) according to the invention.
The invention also relates to a process for preparing a compound of general formula (I), 
wherein
R6 denotes a group of general formula, 
R9 denotes an optionally substituted group xe2x80x94CONHxe2x80x94C1-C10-alkylene or a group selected from among xe2x80x94CONR8xe2x80x94C1-C10-alkyl-Q1, xe2x80x94CONR8xe2x80x94C2-C10-alkenyl-Q1, xe2x80x94CONR8xe2x80x94Q2 and
xe2x80x94COOR8, and
R1-R5, R7, R101, n and X are as hereinbefore defined, characterised in that a compound of general formula (IA) 
wherein
R1 to R5, R7 and R10 are as hereinbefore defined, and
L denotes a leaving group,
is reacted with a primary or secondary amine to form the corresponding amide or is reacted with an alcohol to form the corresponding ester.
The term alkyl groups, including alkyl groups which are a part of other groups, denotes branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1-6, most preferably 1-4 carbon atoms, such as, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Unless otherwise stated, the abovementioned terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all the possible isomeric forms. For example, the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc.
In the abovementioned alkyl groups one or more hydrogen atoms may optionally be replaced by other groups. For example these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkyl group may optionally also be replaced.
Similarly, in the abovementioned alkyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced for example by an optionally substituted group selected from among CN, OCOCH3, aryl, preferably phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine group, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl or cyclopropyl.
The term alkyl bridge, unless otherwise stated, denotes branched and unbranched alkyl groups with 2 to 5 carbon atoms, for example propylene, isopropylene, n-butylene, iso-butyl, sec. butyl and tert.-butyl etc. bridges. Propylene and butylene bridges are particularly preferred. In the alkyl bridges mentioned 1 to 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur.
The term alkenyl groups (including those which are a part of other groups) denotes branched and unbranched alkylene groups with 2 to 10 carbon atoms, preferably 2-6 carbon atoms, most preferably 2-3 carbon atoms, provided that they have at least one double bond. Examples include: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise stated, the abovementioned terms propenyl, butenyl, etc also include all the possible isomeric forms. For example, the term butylene includes n-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1,1-dimethylethenyl, 1,2-dimethylethenyl etc.
In the abovementioned alkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkenyl group may optionally also be replaced.
The term alkynyl groups (including those which are a part of other groups) denotes branched and unbranched alkynyl groups with 2 to 10 carbon atoms, provided that they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynyl or propynyl.
In the abovementioned alkynyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkynyl group may optionally also be replaced.
The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise stated, may carry one or more of the following substituents, for example: OH, NO2, CN, xe2x80x94OCHF2, xe2x80x94OCF3, xe2x80x94NH2, halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, C1-C10-alkyl, preferably C1-C5-alkyl, preferably C1-C3-alkyl, most preferably methyl or ethyl, xe2x80x94Oxe2x80x94C1-C3-alkyl, preferably xe2x80x94O-methyl or xe2x80x94O-ethyl, xe2x80x94N-methyl-tetrahydro-oxazinyl, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-C4-alkyl, preferably xe2x80x94COOCH2CH3, xe2x80x94COOxe2x80x94C(CH3)3 or xe2x80x94COOCH3, xe2x80x94CONH2, xe2x80x94CONHxe2x80x94C1-C10-alkyl, while this alkyl may optionally be further substituted, optionally substituted xe2x80x94CONHxe2x80x94C3-C6-cycloalkyl, preferably optionally substituted xe2x80x94CONH-cyclopentyl, optionally substituted xe2x80x94CONH-heterocycloalkyl, preferably piperidinyl, pyrrolidinyl or piperazinyl, optionally substituted xe2x80x94CONH-heteroaryl, preferably optionally substituted xe2x80x94CONH-pyridyl, optionally substituted xe2x80x94CONH-aryl, preferably optionally substituted xe2x80x94CONH-phenyl, xe2x80x94CONMeC1-C3-alkyl, while this alkyl may optionally be further substituted, preferably xe2x80x94CONMeCH2-pyridyl, benzimidazole or a group of formula 
Examples of 5-10-membered mono- or bicyclic heteroaryl rings wherein up to three C-atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur include furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole and oxadiazole, while each of the abovementioned heterocycles may optionally also be annellated onto a benzene ring, preferably benzimidazole, and unless otherwise stated these heterocycles may for example carry one or more of the following substituents: OH, NO2, CN, xe2x80x94OCHF2, xe2x80x94OCF3, xe2x80x94NH2, halogen, preferably fluorine or chlorine, C1-C10-alkyl, preferably C1-C5-alkyl, preferably C1-C3-alkyl, most preferably methyl or ethyl, xe2x80x94Oxe2x80x94C1-C3-alkyl, preferably xe2x80x94O-methyl or xe2x80x94O-ethyl, -methyl-N-tetrahydro-oxazinyl, xe2x80x94COOH, xe2x80x94COOxe2x80x94C1-C4-alkyl, preferably xe2x80x94COOxe2x80x94C(CH3)3 or xe2x80x94COOCH3, xe2x80x94CONH2, optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl or pyrazinyl, xe2x80x94CONHxe2x80x94C1-C10-alkyl, while this alkyl may itself optionally be substituted, optionally substituted xe2x80x94CONHxe2x80x94C3-C6-cycloalkyl, preferably optionally substituted xe2x80x94CONH-cyclopentyl, optionally substituted xe2x80x94CONH-heteroaryl, preferably optionally substituted xe2x80x94CONH-pyridyl, optionally substituted xe2x80x94CONH-aryl, preferably optionally substituted xe2x80x94CONH-phenyl, xe2x80x94CONMeC1-C3-alkyl, while this alkyl may itself optionally be substituted, preferably xe2x80x94CONMeCH2-pyridyl, benzimidazole or a group of formula 
The term cycloalkyl groups denotes, for example, saturated or unsaturated cycloalkyl groups with 3-8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, while each of the abovementioned cycloalkyl groups may optionally also carry one or more substituents, preferablyxe2x95x90O, or may be annellated to a benzene ring.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
The term heterocycloalkyl groups, unless otherwise described in the definitions, may denote 5-, 6- or 7-membered, saturated or unsaturated heterocycles, which may contain nitrogen, oxygen or sulphur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranon, xcex3-butyrolactone, xcex1-pyran, xcex3-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, while the heterocycle may optionally be substituted.
Generally, the term halogen denotes fluorine, chlorine, bromine or iodine.
The leaving group L denotes either identical or different leaving groups such as for example chlorine, bromine, iodine, methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl, preferably chlorine.
The compounds according to the invention may be present in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers and also in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acidsxe2x80x94such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.
The substituent R1 may denote a group selected from among hydrogen, NH2, XH, preferably OH, halogen, preferably fluorine or chlorine and a C1-C3-alkyl group optionally substituted by one or more, preferably one, two or three halogen atoms, preferably fluorine or chlorine, preferably methyl or ethyl. Most preferably, the substituent R1 is hydrogen.
The substituent R2 may denote a group selected from among hydrogen, CHO, XH, preferably OH, xe2x80x94Xxe2x80x94C1-C2-alkyl, preferably xe2x80x94Oxe2x80x94CH3 or xe2x80x94Oxe2x80x94CH2CH3, and an optionally substituted C1-C3-alkyl group, while the alkyl group preferably consists of 1 to 2 carbon atoms, particularly preferably a carbon atom and may optionally be substituted, preferably by halogen atoms, most preferably by fluorine atoms. In particular, the substituent R2 denotes methyl.
The substituents R3 and R4 may be identical or different and may represent a group selected from among optionally substituted C1-C10-alkyl, preferably C1-C6-alkyl, preferably C1-C4-alkyl, most preferably methyl, ethyl or propyl, particularly preferably methyl or ethyl, C2-C10-alkenyl, preferably ethenyl or propenyl, preferably ethenyl, C2-C10-alkynyl, preferably ethynyl or propynyl, aryl, preferably optionally substituted phenyl, heteroaryl, C3-C8-cycloalkyl, preferably cyclopropyl and cyclobutyl, C3-C8-heterocycloalkyl, xe2x80x94X-aryl, xe2x80x94X-heteroaryl, xe2x80x94X-cycloalkyl, xe2x80x94X-heterocycloalkyl, xe2x80x94NR8-aryl, xe2x80x94NR8-heteroaryl, xe2x80x94NR8-cycloalkyl and
xe2x80x94NR8-heterocycloalkyl, or
a group selected from among hydrogen, halogen, COXR8, CON(R8)2, COR8 and
XR8, preferably hydrogen, or
the groups R3 and R4 may together denote a 2- to 5-membered alkyl bridge, preferably an ethylene, propylene or butylene bridge, while the propylene or butylene bridge may contain 1 to 2 heteroatoms, preferably oxygen , nitrogen or sulphur, most preferably an ethylene bridge.
Most preferably, the substituent R3 denotes methyl or ethyl. The substituent R4 most preferably denotes hydrogen or methyl. Particularly preferred are compounds wherein R3 and R4 represent methyl.
All the groups mentioned in the definition of R3 and R4 may optionally be substituted.
The group R5 may contain hydrogen or a group selected from among optionally substituted C1-C10-alkyl, for example C1-C6-alkyl-aryl or C1-C6-alkyl-heteroaryl, preferably C1-C6-alkyl, most preferably C1-C5-alkyl, particularly preferably propyl, butyl, pentyl, hexyl, xe2x80x94CH2-cyclohexyl, (CH2)1-2 cyclopropyl or (CH2)4xe2x80x94OCOCH3, C2-C10-alkenyl, preferably propenyl, butenyl, pentenyl or hexenyl, preferably propenyl or hexenyl, C2-C10-alkynyl, preferably propynyl, butynyl or pentynyl, preferably propynyl, aryl, preferably phenyl, heteroaryl, xe2x80x94C3-C6-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and xe2x80x94C3-C6-cycloalkenyl, preferably cyclohexenyl or cyclopentenyl, or the substituents R3 and R5 or R4 and R5 together denote a saturated or unsaturated C3-C4-alkyl bridge which may contain 1 to 2 heteroatoms, preferably oxygen, sulphur or nitrogen.
All the groups mentioned in the definition of R5 may optionally be substituted.
The substituent R6 may denote optionally substituted aryl, or heteroaryl, preferably aryl, preferably phenyl.
Most preferably, the substituent R6 denotes a phenyl group, which may be substituted by one of the groups R9 and R10 described hereinafter, while the phenyl ring may carry one of the groups R9, preferably in the para position, and one, two, three or four, preferably one or two, of the groups R10, preferably in the ortho or meta position.
The substituent R7 may denote hydrogen or xe2x80x94COxe2x80x94Xxe2x80x94C1-C4-alkyl, preferably hydrogen.
X denotes, in each case independently of one another, O or S, preferably O.
The groups R8 mentioned in the definitions of the substituents R3 and R4 represent, independently of one another in each case, hydrogen or a group selected from among optionally substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and phenyl, preferably hydrogen or C1-C2-alkyl.
The substituent R9 may represent a group selected from among optionally substituted C1-C6-alkyl, preferably C1-C4-alkyl, preferably methyl, ethyl or propyl, most preferably methyl, C2-C6-alkenyl, C2C6-alkynyl, xe2x80x94CONHxe2x80x94C1-C10-alkylene, preferably xe2x80x94CONHxe2x80x94C1-C3-alkylene, preferably xe2x80x94CONHxe2x80x94C1-C2-alkylene, xe2x80x94O-aryl, preferably Oxe2x80x94C6-C10-aryl, most preferably O-phenyl, xe2x80x94O-heteroaryl, xe2x80x94O-cycloalkyl, preferably Oxe2x80x94C3-C6-cycloalkyl, most preferably O-cyclopropyl, xe2x80x94O-heterocycloalkyl, aryl, preferably C6-C10-aryl, most preferably phenyl, heteroaryl, cycloalkyl, preferably C3-C6-cycloalkyl, most preferably cyclopropyl, and heterocycloalkyl, or a group selected from among xe2x80x94Oxe2x80x94C16-alkyl-Q1, xe2x80x94CONR8xe2x80x94C1-C10-alkyl-Q1, xe2x80x94CONR8xe2x80x94C1-C10-alkenyl-Q1, xe2x80x94CONR8xe2x80x94Q2, halogen, for example fluorine, chlorine, bromine or iodine, OH, xe2x80x94SO2R8, xe2x80x94SO2N(R8)2, xe2x80x94COR8, xe2x80x94COOR8, xe2x80x94N(R8)2, xe2x80x94NHCOR8, CONR8OC1-C10-alkylQ1 and CONR8OQ2, where Q1 and Q2 are as hereinbefore defined.
Preferably, R9 denotes one of the following groups xe2x80x94CONHxe2x80x94C1-C10-alkyl, preferably xe2x80x94CONHxe2x80x94C1-C3-alkyl, most preferably xe2x80x94CONHxe2x80x94C1-C2-alkyl, while this alkyl may itself optionally be substituted, by CN, optionally substituted aryl, preferably optionally substituted phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine group, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl. Moreover R9 preferably denotes xe2x80x94CONH-heteroaryl, preferably xe2x80x94CONH-pyridyl, xe2x80x94CONHxe2x80x94C3-C10-cycloalkyl, preferably xe2x80x94CONH-cyclopropyl xe2x80x94CONH-cyclobutyl or xe2x80x94CONH-cyclopentyl, most preferably xe2x80x94CONH-cyclopropyl; xe2x80x94CONHxe2x80x94C3-C10-heterocycloalkyl , xe2x80x94CONHxe2x80x94C6-C10-aryl, preferably xe2x80x94CONH-phenyl, COOxe2x80x94C1-C3-alkyl, most preferably COOCH3, COOH, halogen, preferably F or chlorine, OH or a group of formula 
All the groups mentioned in the definition of R9 may optionally be substituted, preferably by one or more of the groups selected from among OH, OCH3, Cl, F, CH3, COOH, CONHCH2Ph and CONHCH2-pyrazinyl-CH3.
The substituent R10 may be identical or different in each case and may denote a group selected from among optionally substituted C1-C6-alkyl, preferably C1-C3-alkyl, C2-C6-alkenyl, preferably C2-C3-alkenyl and C2-C6-alkynyl, preferably C2-C3-alkynyl, xe2x80x94Oxe2x80x94C1-C6-alkyl, preferably xe2x80x94Oxe2x80x94C1-C3-alkyl, xe2x80x94Oxe2x80x94C2-C6-alkenyl, xe2x80x94Oxe2x80x94C2C6-alkynyl, C3-C6-heterocycloalkyl and C3-C6-cycloalkyl, or a group selected from among hydrogen, xe2x80x94CONH2, xe2x80x94COOR8, xe2x80x94OCON(R8)2, xe2x80x94N(R8)2, xe2x80x94NHCOR8, xe2x80x94NHCON(R8)2, xe2x80x94NO2 and halogen, for example fluorine, chlorine, bromine or iodine.
Preferably, the substituent R10 denotes hydrogen, methyl, methoxy, fluorine or chlorine, most preferably hydrogen or methoxy, particularly preferably methoxy.
Adjacent groups R9 and R10 may together denote a bridge of general formula 
wherein
Y denotes O, S or NR11, preferably NR11,
m denotes 0, 1 or 2, preferably 1,
R11 denotes hydrogen or C1-C2-alkyl, preferably hydrogen or methyl, most preferably hydrogen,
R12 denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, xe2x80x94C1-C3-alkyl-phenyl, xe2x80x94C1-C3-alkyl-pyridyl, xe2x80x94C1-C3-alkyl-pyrazinyl, xe2x80x94C1-C3-alkyl-pyrimidinyl and xe2x80x94C1-C3-alkyl-pyridazinyl, preferably phenyl, pyridyl and pyrazinyl, and
R13 denotes C1-C6-alkyl, preferably methyl or ethyl.